NM_198859.4:c.816T>C

Variant names:

• chr3-64147674-A-G
• rs27673
• NM_198859.4:c.816T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198859.4(PRICKLE2):​c.816T>C​(p.Asp272Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.995 in 1,613,902 control chromosomes in the GnomAD database, including 799,631 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74145 hom., cov: 33)
  • Exomes 𝑓: 1.0 (725486 hom.)
• Consequence: PRICKLE2 NM_198859.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.979
• Publications: 14 publications found

Genes affected

PRICKLE2 (HGNC:20340): (prickle planar cell polarity protein 2) This gene encodes a homolog of Drosophila prickle. The exact function of this gene is not known, however, studies in mice suggest that it may be involved in seizure prevention. Mutations in this gene are associated with progressive myoclonic epilepsy type 5. [provided by RefSeq, Dec 2011]

PRICKLE2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 3-64147674-A-G is Benign according to our data. Variant chr3-64147674-A-G is described in ClinVar as Benign. ClinVar VariationId is 130137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.979 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198859.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRICKLE2	NM_198859.4	MANE Select	c.816T>C	p.Asp272Asp	synonymous	Exon 7 of 8	NP_942559.1	Q7Z3G6
	PRICKLE2	NM_001370528.1		c.816T>C	p.Asp272Asp	synonymous	Exon 7 of 8	NP_001357457.1	Q7Z3G6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRICKLE2	ENST00000638394.2	TSL:1 MANE Select	c.816T>C	p.Asp272Asp	synonymous	Exon 7 of 8	ENSP00000492363.1	Q7Z3G6
	PRICKLE2	ENST00000295902.11	TSL:5	c.984T>C	p.Asp328Asp	synonymous	Exon 8 of 9	ENSP00000295902.7	A0A1X7SBR1
	PRICKLE2	ENST00000906078.1		c.816T>C	p.Asp272Asp	synonymous	Exon 7 of 9	ENSP00000576137.1

Frequencies

GnomAD3 genomes AF: 0.986 AC: 150138 AN: 152202 Hom.: 74089 Cov.: 33

Gnomad AFR AF: 0.958

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.993

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 0.999

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.997

Gnomad OTH AF: 0.989

GnomAD2 exomes AF: 0.995 AC: 246851 AN: 248062 AF XY: 0.996

Gnomad AFR exome AF: 0.954

Gnomad AMR exome AF: 0.995

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.999

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.996

GnomAD4 exome AF: 0.996 AC: 1456230 AN: 1461582 Hom.: 725486 Cov.: 61 AF XY: 0.997 AC XY: 724608 AN XY: 727106

African (AFR) AF: 0.959 AC: 32092 AN: 33478

American (AMR) AF: 0.995 AC: 44513 AN: 44724

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26136 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39699 AN: 39700

South Asian (SAS) AF: 1.00 AC: 86230 AN: 86258

European-Finnish (FIN) AF: 0.999 AC: 53084 AN: 53128

Middle Eastern (MID) AF: 0.996 AC: 5746 AN: 5768

European-Non Finnish (NFE) AF: 0.997 AC: 1108684 AN: 1111994

Other (OTH) AF: 0.994 AC: 60046 AN: 60396

GnomAD4 genome AF: 0.986 AC: 150253 AN: 152320 Hom.: 74145 Cov.: 33 AF XY: 0.987 AC XY: 73487 AN XY: 74480

African (AFR) AF: 0.958 AC: 39806 AN: 41566

American (AMR) AF: 0.993 AC: 15207 AN: 15312

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5160 AN: 5160

South Asian (SAS) AF: 1.00 AC: 4826 AN: 4826

European-Finnish (FIN) AF: 0.999 AC: 10616 AN: 10622

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 0.997 AC: 67867 AN: 68040

Other (OTH) AF: 0.989 AC: 2093 AN: 2116

Alfa AF: 0.992 Hom.: 48653

Bravo AF: 0.985

Asia WGS AF: 0.998 AC: 3470 AN: 3478

EpiCase AF: 0.998

EpiControl AF: 0.998

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Progressive myoclonic epilepsy type 5 (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.025
DANN	Benign	0.27
PhyloP100		-0.98
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs27673; hg19: chr3-64133350; COSMIC: COSV108095867;